WASHINGTON — Lawyers for three condemned Oklahoma prisoners who claimed that the three-drug combination that could be used to execute them risked causing unconstitutional pain and suffering ran into skepticism from conservative members of the Supreme Court on Wednesday.

The prisoners argued that the sedative midazolam, which was involved in three prolonged and apparently painful executions last year, could not reliably produce a state of deep unconsciousness before other, severely painful drugs were injected. They asked that lower court rulings permitting the use of the drug in executions be overturned.

But several of the conservative justices questioned whether the evidence warranted a reversal and, more broadly, expressed exasperation with shortages of more proven drugs that they said had been caused by opponents of capital punishment.

“Let’s be honest about what’s going on here,” Justice Samuel A. Alito Jr. said. “Executions can be carried out painlessly.”

He added, “Is it appropriate for the judiciary to countenance what amounts to a guerrilla war against the death penalty?”

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Bottles of the sedative midazolam, the initial agent in lethal injections, at a hospital pharmacy in Oklahoma City.CreditSue Ogrocki/Associated Press

Much of the hearing was given over to technical wrangling on scientific studies, with each side accusing the other of misrepresenting the medical literature on the effects of midazolam.

The more liberal members of the court, particularly Justice Elena Kagan and Justice Sonia Sotomayor, spoke in support of the prisoners’ suit, stressing the uncertainty over whether midazolam could reliably induce a deep enough unconscious state to prevent severe suffering as lethal drugs were injected.

“Suppose that we said we’re going to burn you at the stake, but before we do, we’re going to use an anesthetic of completely unknown properties and unknown effects,” said Justice Kagan, who likened the effect of injecting potassium chloride, a heart-stopping agent used in lethal injections in Oklahoma and many other states, to “being burned alive from the inside.”

But Justice Antonin Scalia said that the barbiturates traditionally used, and proved to be reliable, were not obtainable “because the abolitionists have rendered it impossible.”

Chief Justice John G. Roberts Jr. said that in this situation, where each plaintiff is clearly guilty of a capital offense, “you put us in a position of arguing that he can’t be executed.”

Justice Anthony M. Kennedy, who is often the swing vote, spoke little but appeared to share some of the skepticism of the conservatives.

The justices could also decide to send the case back to the district court to re-examine the medical questions.

Wednesday’s hearing, in the case Glossip v. Gross, came one year after a botched execution in Oklahoma drew attention to the mounting problems surrounding lethal injections.

Oklahoma and several other states have turned to midazolam as the initial agent in lethal injections because manufacturers in Europe and the United States have refused to sell them the barbiturates that were traditionally used to render prisoners unconscious.

But midazolam was implicated in three prolonged executions last year in which prisoners appeared to suffer.

Officials in Oklahoma and 14 other states that joined in supporting briefs argue that when properly administered, midazolam does put prisoners into a deep coma. They accuse the prisoners and their lawyers of seeking to prevent all executions and argue that if prisoners object to one drug combination, they should have to specify practical alternatives.

The Supreme Court last examined lethal injections in 2008, in Baze v. Rees, when it held that what was then the standard three-drug combination, using the barbiturate sodium thiopental as the first agent, did not violate the Eighth Amendment’s ban on cruel and unusual punishment.

The court made clear in that ruling, however, that the first drug must prevent the intense pain that can be caused by the second and third drugs, a paralyzing agent and a heart-stopping chemical. And the justices noted that if the first agent did not cause a deep enough level of unconsciousness, the prisoner’s acute pain could be hidden from view once the paralyzing agent was administered and the prisoner was unable to move or speak.

Many legal experts hope that beyond evaluating the legality of midazolam as an execution drug, the court will provide clearer guidelines for lethal injection methods as many states, because of the drug scarcity, try new combinations and purchase drugs from secret sources, including lightly regulated compounding pharmacies. The newly unsettled conditions have resulted in numerous lawsuits and requests for stays of execution, with lower courts offering contradictory rulings.

The current case originally included a fourth inmate, Charles F. Warner. But he was executed on Jan. 15 after the Supreme Court denied his request for a stay by a 5-to-4 vote. Journalists who witnessed the 18-minute execution, using a higher dose of midazolam than was the case with Mr. Lockett, said that Mr. Warner did not seem to suffer great pain and that he appeared to lose consciousness quickly.

Justice Sotomayor, joined by Justice Ruth Bader Ginsburg, Justice Stephen G. Breyer and Justice Kagan, dissented from the denial of a stay for Mr. Warner. The court later decided to hear the appeal of the other three prisoners, a decision that only required the votes of four justices.

If the court does find midazolam to be too unreliable to use in executions, Oklahoma, Florida and other states will have to find sources for other drugs or consider using different methods of execution. Several states are reviving plans to use the electric chair, the firing squad or nitrogen gas as alternatives.

Correction:April 29, 2015

An earlier version of this article quoted Justice Elena Kagan incompletely. She said, “Suppose that we said we’re going to burn you at the stake, but before we do, we’re going to use an anesthetic of completely unknown properties and unknown effects,” not, “Suppose we said we’re going to burn you at the stake, but before we do, we give you an anesthetic with unknown effects.”

A version of this article appears in print on , Section A, Page 16 of the New York edition with the headline: Justices Hear Prisoners’ Lethal Injection Case. Order Reprints | Today’s Paper | Subscribe